Serum total T4 concentrations

Answer The results of the laboratory tests confirm the hypothyroxinemia (i.e., low serum total T4 concentration). The calculated free thyroxine index... 

Serum total T4 concentrations were initially determined indirectly, using methods that measured the amount of iodine in a protein precipitate of serum (protein-bound iodine, PBI). In addition to hormonal iodine, the PBI tests also measured iodoproteins, iodotyrosines, inorganic iodine, and thyroglobulin. More specific T4 procedures involved the measurement of hormonal iodine in either a butanol extract of a serum protein precipitate (butanol-extractable iodine) or in a purified fraction of serum (I4 by column). These methods were useful because the iodine in T4 normally accounts for 80% to 90% of all iodine in serum. Both... 

In thyrotoxic Graves disease, there is an increase in the overall hormone production rate with a disproportionate increase in T3 relative to T4 (Table 20-1). Saturation of thyroid-binding globulin is increased due to the elevated levels of serum T4 and T3, which is reflected in an elevated T3 resin uptake. As a result, the concentrations of free T4, free T3, and the free T4 and T3 indices are increased to an even greater extent than are the measured serum total T4 and T3 concentrations. The TSH level is undetectable due to negative feedback by elevated levels of thyroid hormone at the pituitary. In... 

Co-trimoxazole has been suggested to have some antithyroid activity. However, whether this effect is due to trimethoprim alone is still unclear (1142,1143). Co-trimoxazole 27-31 mg/kg bd orally substantially altered serum total T4 and TSH concentrations and neutrophil counts in dogs within as short a time as a few weeks (1144), and 14—16 mg/kg orally every 12 hours for 3 weeks reduced total and free T4 concentrations and increased the TSH concentration, conditions that would be compatible with hypothyroidism (1145). 

As patients recover from NTIs, many of the thyroid test abnormalities revert to normal. Total T4 concentrations will be corrected first followed by a rise in T3. Serum TSH may also transiently rebound to high concentrations for several days or weeks before returning to normal. Thus, in NTI, abnormal thyroid function test results do not necessarily indicate the presence of thyroid disease, but may demonstrate adaptations to the catabolic state. Conversely, paradoxically normal values may be seen in patients with thyroid disease as a result of medications or nonthyroidal illness per se. Assessments of thyroid function in ill patients are best postponed until the illness resolves, unless a diagnosis would affect patient outcome. 

Unfortunately, FT4 and FTa estimate methods have been found to be unreHable in a number of situations. One of these is familial dysalbuminemic hyperthyroidism, an inherited disorder in which a normally minor component of serum albumin is increased. This variant albumin binds T4 with abnormally high affinity, but its avidity for T3 is not comparably increased. Although total T4 concentrations are usually high, patients with familial dysalbuminemic hyperthyroidism are clinically euthyroid, and free hormone concentrations are normal as measured by reference methods... 

Some concern has been expressed tiiat the Murphy CPBA system for total T4 is not operating optimally as a true satmation analysis and that T4 disequilibrates between TBP and the resin, so that the final result is dependent on the TBP capacity of a serum as well as its total T4 concentration (M2). However, recent studies have indicated that dissociation of the protein-T4 complex is too slow to have a significant effect on the resin separation system (C19). In other words, the use of resins in the CPBA system to separate bound and free T4 is quite valid. Nevertheless, some workers have looked to other media to effect this separation, e.g., Sephadex (C22), but this is not an ideal way, as Sephadex has an affinity for T4 (C19). Columns of Sephadex have also been used to good effect as a substitute for ethanol in separating the T4 from the serum (B14, S7), and such techniques are much simpler than the original and furthermore, result in an almost constant 100 recovery of the T, in the serum compared with the low and variable recovery with ethanol. 

In other studies in nonrenal chronic illness ( sick euthyroid patients), the total T4 levels are found to be low and associated with low TBG activities and either normal or marginally elevated serum-free T4 concentrations (B7). The mechanisms underlying the thyroid hormone changes (particularly of T3) were further elucidated in the very recent paper by Carter et al. (Cl). The most striking abnormality found was a highly significant reduction in both total and free T3 concentrations in the... 

Total T4 and FT4E measurements are not ideal indicators of thyroid status, in part because of the effects of variations in serum binding protein concentrations, but also because T3 is the biologically active and most potent form of thyroid hormone and because the relationships between these hormones (T4 and T3) are not always predictable. In patients with hyperthyroidism, T3 is usually elevated to a greater extent than T4 because it is derived from two sources increased thyroidal secretion of T3 and increased peripheral conversion of T4 to T3. The measurement of total T3 is sometimes a useful adjunct test in patients suspected of hyperthyroidism. However, because T3 concentrations fluctuate rapidly in response to stress and other nonthyroidal factors, T3 concentrations are low not only in hypothyroidism, but also in many other conditions. Thus the routine measurement of total T3 is not a good screening test of thyroid status. 

T4 and Ta circulate in the blood as equilibrium mixtures of free and protem-bound hormones. Thus changes in the concentration or affinity of TBG or other transport proteins profoundly affect the total hormone concentration in serum. Alternatively the steady-state concentration of the free hormone is independent of these binding protein variations and remains almost constant. 

The THBR is derived from a version of the T3 or T4 uptake test. Uptake tests are used to estimate the number of unoccupied (unsaturated) thyroid hormone bindhig sites on serum proteins. This information is important because variations in total thyroid hormone concentrations in blood, as discussed previously, have resulted from changes in binding protein concentrations. Values obtained by uptake methods are expressed as a THBR, which is directly proportional to the free hormone fraction (within limits). Measurement of THBR, in conjunction with a total hormone concentration, is a clinically useful indirect method for calculating the FT4 (or FT3) index. The index approach is particularly useful in patients with nonthyroidal illness in whom FT4 immunoassay methodologies are unreliable. Specifically, TT4 measurement is more diagnostically useful in such patients provided that values are interpreted in accord with the severity of illness in the patient that is indirectly reflected by abnormalities in THBR. 

Reference intervals are numerically close to the normal intervals for total T4 or T3. Most automated immunoassay analyzers are capable of performing the THBR and total T4 tests with online calculation of the FT4 index. Theoretically, because the calculated indices are products of T4 or T3 concentrations and a ratio, they have concentration units. However, to avoid confusion with serum T4 or T3, the free hormone index units are usually omitted or termed index units. Typical values are as follows ... 

Calculation of T4/TBG and T3/TBG Ratios Measurements of serum TBG concentration have been used in the diagnosis of thyroid disease in two ways. The most common approach is to calculate a T4 TBG or T3 TBG ratio. Such indices are derived from mass action equations and are used to approximate FT4 or FT3 concentrations. These ratios correlate variably with FT4 or FT3 concentrations and are particularly useful in sera with altered TBG concentrations however, they may fail to compensate for TBG variants with reduced T4 affinity or for abnormal albumin binding. The reference interval for T4 TBG ratios is 3.8 to 4.5 when the reference intervals for total T4 and TBG are 4.5 to 12.5 pg/dL and 1.2 to 2.8 mg/dL, respectively. 

Measurements of TBG also have been used to derive values for FT4 or FT3 by calculation. Assuming TBG is the major determinant of thyroid hormone binding, serum concentrations of TBG and total T4 (or T3), together with the association constant for the binding of T4 (or T3) to TBG, are used to calculate values of the free hormone. In most cases, these calculated values correlate well with those directly determined. 

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